Cocaine has rapidly become a major drug of abuse and the problems associated with its use have prompted such characterizations as """"""""a national epidemic"""""""". The neurochemical properties of cocaine which mediate its immense abuse potential are not understood, yet considerable attention has been focused on the catecholamine (CA) neuronal system. Cocaine blocks uptake of the biogenic amine neurotransmitters and its greatest potency in this regard is expressed in serotonin (5HT) neurons. Cocaine also inhibits the activity of CA and 5HT containing neurons and its potency and duration of action is also greatest on 5HT cells. Surprisingly little information is available on the actions of cocaine on 5HT neurochemistry. The long term objectives of this proposal are to define the effects of acute and chronic cocaine on 5HT neurons and delineate the persistency of its effects on the 5HT system following withdrawal. Emphasis will be placed on determining how cocaine modulates the synaptic availability of 5HT through analyses of synthesis, release, and re-uptake. The proposal has three interrelated aims which are directed at determining the time course and brain regional effects of cocaine on 5HT neurochemistry. In one aim, binding of 3H-paroxetine will be used to determine if cocaine alters either the affinity of the 5HT transporter for 5HT or the number of active transporters. Tryptophan hydroxylase (TPH) is the initial and rate limiting enzyme in the synthesis of 5HT and the influence of cocaine on its activity, kinetic properties, and responsiveness to phosphorylating conditions, which normally activate TPH, are also part of the first aim.
A second aim will examine the effects of cocaine on tryptophan uptake, its synthesis to 5HT by TPH, and metabolism of 5HT to 5HIAA. The functional status of the 5HT transporter after cocaine will be assessed through measures of 5HT uptake and storage.
A third aim will assess the effects of cocaine on release of endogenous 5HT from superfused slices with emphasis on the receptor systems which regulate release. It is hypothesized that the overall effect of cocaine on 5HT is to increase its synaptic availability and activity. The health relatedness of this proposal derives from the current development of several 5HT selective compounds, including tryptophan and fluoxetine, as cocaine treatment agents in the NIDA Drug Development Program. At least fluoxetine has now been reported to reduce cocaine self administration in animals. The studies in this proposal will provide needed information on the neurobiological substrates of cocaine abuse through a multifaceted approach to the study of 5HT-cocaine interactions. Further development of 5HT-interacting compounds, like tryptophan and fluoxetine, to correct cocaine induced neurochemical imbalances in 5HT will be facilitated through a better understanding of the effects of cocaine on all aspects of 5HT neurochemistry.
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| D'Sa, C M; Arthur Jr, R E; Kuhn, D M (1996) Expression and deletion mutagenesis of tryptophan hydroxylase fusion proteins: delineation of the enzyme catalytic core. J Neurochem 67:917-26 |
| D'Sa, C M; Arthur Jr, R E; States, J C et al. (1996) Tryptophan hydroxylase: cloning and expression of the rat brain enzyme in mammalian cells. J Neurochem 67:900-6 |
